1,2-diarylmethylene derivatives, their methods of preparation and their uses in therapeutics

ABSTRACT

The present invention relates to the derivatives of formula: ##STR1## and to their use in therapeutics, especially as drugs with anti-inflammatory and analgesic properties.

CROSS REFERENCE TO RELATED APPLICATION

This is a continuation-in-part application of U.S. Ser. No. 08/822,842filed on Mar. 24, 1997, now U.S. Pat. No. 5,840,753.

The present invention relates to the 1,2-diarylmethylene derivatives ofgeneral formula (I) below and their addition salts, particularlypharmaceutically acceptable addition salts, as novel products.

One of the arachidonic acid biotransformation pathways is thecyclooxygenase pathway, which makes it possible to transform arachidonicacid to PGG2 and then PGH2. Recent work on the cloning and sequencing ofcyclooxygenase has revealed the presence of two isoenzymes, namelycyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), in severalspecies and particularly in man. The first is a constitutive enzymewhich is expressed in the majority of tissues, while the second, whichis expressed in a few tissues such as the brain, is inducible in themajority of tissues by numerous products, in particular by the cytokinesand the mediators produced during the inflammatory reaction. Each enzymehas a different role and the inhibition of COX-1 or COX-2 will not haveidentical consequences. The inhibition of COX-1 will cause a decrease inthe prostaglandins participating in homeostasis which can give rise toside effects. The inhibition of COX-2 will cause a decrease in theprostaglandins produced in an inflammatory situation. Thus the selectiveinhibition of COX-2 makes it possible to obtain a well-toleratedanti-inflammatory.

The compounds of the invention make it possible to achieve thisselective inhibition. The compounds in question consequently have a veryvaluable pharmacological profile insofar as they possessanti-inflammatory and analgesic properties while being remarkably welltolerated, especially in gastric terms. They will be particularlyindicated in the treatment of inflammatory phenomena and in thetreatment of pain.

An example of their use which may be mentioned is the treatment ofarthritis, especially rheumatoid arthritis, spondylitis, goutyarthritis, osteoarthritis, juvenile arthritis, autoimmune diseases andlupus erythematosus. They will also be indicated in the treatment ofbronchial asthma, dysmenorrhea, tendinitis, bursitis, dermatologicalinflammations such as psoriasis, eczema, burns and dermatitis. They canalso be used in the treatment of gastrointestinal inflammations, Crohn'sdisease, gastritis and ulcerative colitis, in the prevention of cancer,especially adenocarcinoma of the colon, in the prevention ofneurodegenerative diseases, particularly Alzheimer's disease, in theprevention of stroke and epilepsy, and in the prevention of prematurelabour.

Their analgesic properties also enable them to be used for any painsymptoms, especially in the treatment of myalgia, articular pain orneuralgia, dental pain, herpes zoster and migraine, in the treatment ofrheumatic complaints and pain of cancerous origin, and also ascomplementary treatments for infectious and febrile states.

The present invention further relates to the method for the preparationof the said products and to their application in therapeutics.

These diarylmethylene derivatives are characterised in that they havethe general formula (I): ##STR2## in which: R represents:

a lower alkyl radical having from 1 to 6 carbon atoms,

a lower haloalkyl radical having from 1 to 6 carbon atoms,

an --NH₂ group,

A represents:

an aromatic ring: ##STR3## in which X₁, X₂ and X₃ independentlyrepresent: a hydrogen atom,

a halogen atom,

a lower alkyl radical having from 1 to 6 carbon atoms,

a lower O-alkyl radical having from 1 to 6 carbon atoms,

a trifluoromethyl radical,

or even two of these can form together a methylene dioxy group,

A can also represent a thiophene or pyridine heterocycle ##STR4## inwhich X₁, X₂ and X₃ have the same meanings as above, Y represents:

a --CO₂ R₁ group in which R₁ is a hydrogen atom or a lower alkyl radicalhaving from 1 to 6 carbon atoms,

a --CH₂ OH group as well as their addition salts, in particular theirpharmaceutically acceptable addition salts.

In the description and the claims, <<lower alkyl >> is understood asmeaning a linear or branched hydrocarbon chain having from 1 to 6 carbonatoms. A lower alkyl radical is for example a methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tertbutyl, pentyl, isopentyl, hexyl orisohexyl radical.

<<Lower haloalkyl radical >> is understood as meaning an alkyl radicalhaving from 1 to 6 carbon atoms of which 1 to 7 hydrogen atoms have beensubstituted with 1 to 7 halogen atoms. A lower haloalkyl radical is forexample a trifluoromethyl radical, a 2,2,2-trifluoroethyl radical, apentafluoroethyl radical, a 2,2-difluoro-3,3,3-trifluoropropyl radical,a heptafluoropropyl radical, a chloromethyl or a bromomethyl radical.

<<Halogen >> is understood as meaning a chlorine, bromine, iodine orfluorine atom.

The derivatives according to the invention are advantageously thederivatives of formula (I) above in which:

R represents:

a methyl radical,

an --NH₂ group,

A represents an aromatic ring: ##STR5## in which X₁ and X₂ independentlyrepresent: a hydrogen atom,

a halogen atom,

a lower O-alkyl radical having from 1 to 6 carbon atoms,

a lower alkyl radical having from 1 to 6 carbon atoms,

Y represents:

a --CO₂ R₁ group in which R₁ is a hydrogen atom or a lower alkyl radicalhaving from 1 to 6 carbon atoms, or

a CH₂ OH group.

Within the framework of the present invention, it will be advantageousto use a compound of formula (I) in which at least one of the followingconditions is satisfied:

R represents a methyl radical or an --NH₂ group,

A represents an aromatic ring: ##STR6## in which X₁ represents achlorine or fluorine atom and X₂ represents a hydrogen atom or achlorine atom,

Y represents a --COOC₂ H₅ group or a --COOH group which can be salified.

The particularly preferred compounds of the invention are those whichare selected from the following compounds:

Ethyl(Z)-3-(3,5-dichlorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate##STR7## Sodium(E)-3-(4-fluorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate##STR8##(E)-3-(4-fluorophenyl)-3-(4-sulphamoylphenyl)-2-(2-hydroxyethyl)prop-2-enoicacid ##STR9## Sodium(Z)-3-(4-chlorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate##STR10##

According to the invention, the compounds of formula (I) can besynthesised in the following way:

By a Friedel-Crafts reaction of the acid chloride of formula (II)

    A--COCl                                                    Formula (II)

in which A is defined as above, with an alkylthiophenol or ahaloalkylthiophenol of formula: ##STR11## in which R' is a lower alkylor lower haloalkyl radical, the ketones of formula (III) ##STR12##

Formula (III)

in which A and R' are defined as above, are obtained.

The treatment of these ketones with an oxidising agent such as, forexample meta-chloroperbenzoic acid or sodium perborate, gives thecompounds of formula (IV): ##STR13##

Formula (IV)

in which A and R' are defined as above.

The treatment of these ketones of formula (IV) with a succinic acidester of formula R'₁ OOCCH₂ CH₂ COOR'₁, in which R'₁ is a lower alkylradical having from 1 to 6 carbon atoms, according to the Stobbereaction in tert-butanol in the presence of sodium or potassiumtert-butoxide or other sodium or potassium alkoxide, or even in toluenein the presence of sodium hydride, gives a mixture of two stereoisomersof formulae (V) and (V'): ##STR14## in which A, R' and R'₁ are definedas above.

These two stereoisomers can be separated by fractional recrystallisationof the mixture or by fractional recrystallisation of a salt of the acid,such as a sodium salt, a potassium salt or an amine salt, in particularan optically active amine such as R-(+)-1-phenylethylamine orS-(-)-1-phenylethylamine.

The choice of the basic condensation agent and solvent in which theStobbe reaction takes place can also drive this reaction preferentiallytowards the Z isomer or the E isomer.

The selective reduction of the acid function of the products of formula(V) thus separated, for example by the action of borane or one of itscomplexes such as the borane/dimethyl sulphide complex, or even by theaction of borane prepared in situ by the action of an acid on a sodiumor potassium borohydride in a solvent such as tetrahydrofuran, glyme,diglyme or triglyme, gives the alcohol esters of formula (I): ##STR15##in which A and R' are defined as above.

The hydrolysis of the ester function with sodium hydroxide in refluxingethanol for example, gives the derivatives of formula (I): ##STR16## inwhich A and R' are defined as above.

The compounds of formula (I) in which R is an --NH₂ group can beprepared according to the following reaction scheme, in which Phrepresents a phenyl group, R'₁ is defined as above and Z represents anMgBr radical when A is a ring derived from phenyl or thiophene and Zrepresents Li when A is a ring derived from pyridyl: ##STR17##

The compounds of formula (VI) are separated and reduced in the same wayas the compounds of formula (V) which leads to the compounds of formula(VII): ##STR18##

Formula (VII)

in which A and R'₁ are defined as above,

the compounds of formula (VII) are treated with trifluoroacetic acidunder reflux to give the lactone derivatives of formula (VIII):##STR19##

Formula (VIII)

in which A is defined as above.

The compounds of formula (VIII) are hydrolysed in basic medium to givethe compounds of formula (I) in which R represents a NH₂ group and Y aCOOH group.

The compounds of the invention of formula (I) in which R represents anNH₂ group can also be obtained from corresponding derivatives of formula(I) in which A and Y are defined as above and R represents a methylgroup by any of the methods of transforming a methanesulphone group intoa sulphonamide group known in the literature such as, for example, thatdescribed in Tetrahedron Letters, 1994, 39 (35), 7201 and which consistsin reacting the methanesulphones with a base and a trialkylborane in anorganic solvent such as tetrahydrofuran under reflux followed by theaction of hydroxylamine O-sulphonic acid.

The compounds of formula (I) in which Y represents a --COOR₁ group canbe obtained from the corresponding derivatives in which Y represents a--COOH group by esterification according to known methods, for exampleby the treatment with an alcohol under reflux in the presence ofhydrogen chloride gas.

The compounds of formula (I) in which Y represents a --CH₂ OH group canbe obtained from corresponding compounds of formula (I) in which Yrepresents a --COOR₁ group, by reduction according to the methods knownto the person skilled in the art, such as, for example the action of aborohydride or lithium aluminium hydride in tetrahydrofuran, animplementation variant consisting in hydrolysing the ester function ofthe acid ester of formula (V) in a basic medium, and reducing the diacidobtained with borane or one of its complexes.

The compounds of formula (I) such as defined above as well as theiraddition salts, in particular their pharmaceutically acceptable additionsalts, are cyclooxygenase-2 inhibitors and possess a very goodanti-inflammatory and analgesic activity coupled with an excellenttolerance, particularly gastric tolerance.

These properties justify their application in therapeutics and theinvention further relates, by way of drugs, to the products as definedby formula (I) above as well as their addition salts, in particulartheir pharmaceutically acceptable addition salts.

The addition salts of certain compounds of formula (I), in particularthose which have an acid function, can be obtained by the reaction ofthese compounds with a base or with an amino acid according to a methodknown per se. Amongst the bases which can be used, sodium hydroxide,potassium hydroxide, potassium or sodium carbonate and sodium orpotassium bicarbonate can be mentioned, and amongst the amino acids,lysine for example.

Thus, the invention also covers a pharmaceutical compositioncharacterised in that it comprises a pharmaceutically effective amountof at least one compound of formula (I) such as defined above or one ofits pharmaceutically acceptable addition salts incorporated in apharmaceutically acceptable excipient, vehicle or carrier.

These compositions can be administered by the buccal, rectal,parenteral, transdermal, ocular, nasal or auricular route.

These compositions can be solid or liquid and can be presented in thepharmaceutical forms commonly used in human medicine, for example simpleor coated tablets, gelatine capsules, granules, suppositories,injectable preparations, transdermal systems, eye drops, aerosols andsprays, and ear drops. They are prepared by the customary methods. Theactive principle, which consists of a pharmaceutically effective amountof at least one compound of formula (I) as defined above or one of itspharmaceutically acceptable addition salts can be incorporated thereintogether with excipients normally employed in pharmaceuticalcompositions, such as talc, gum arabic, lactose, starch, magnesiumstearate, polyvidone, cellulose derivatives, cocoa butter,semi-synthetic glycerides, aqueous or non-aqueous vehicles, fats ofanimal or vegetable origin, glycols, various wetting agents, dispersantsor emulsifiers, silicone gels, certain polymers or copolymers,preservatives, flavourings and colours.

The invention also covers a pharmaceutical composition withanti-inflammatory and analgesic activity which can be used especially asa favourable treatment for inflammatory phenomena and pain, saidcomposition being characterised in that it comprises a pharmaceuticallyeffective amount of at least one compound of formula (I) above or one ofits pharmaceutically acceptable addition salts incorporated in apharmaceutically acceptable excipient, vehicle or carrier.

In one embodiment, a pharmaceutical composition with anti-inflammatoryand analgesic activity is prepared which may be used especially as afavourable treatment for various inflammations and pain.

The invention also covers a pharmaceutical composition useful in theprevention of cancer, in particular adenocarcinoma of the colon, in theprevention of neurodegenerative diseases, particularly Alzheimer'sdisease, in the prevention of stroke and epilepsy, and in the preventionof premature labour.

In one implementation variant, a composition is formulated as gelatinecapsules or tablets containing a dose of 1 mg to 1000 mg, or asinjectable preparations containing a dose of 0.1 mg to 500 mg. It isalso possible to use compositions formulated as suppositories,ointments, creams, gels, aerosol preparations, transdermal preparationsor plasters.

The invention also covers a method of therapeutic treatment for mammals,characterised in that a therapeutically effective amount of at least onecompound of formula (I) as defined above or one of its pharmaceuticallyacceptable addition salts is administered to the said mammal. In onevariant of this method of treatment, the compound of formula (I) eitherby itself or in association with a pharmaceutically acceptableexcipient, is formulated as gelatine capsules or tablets containing adose of 1 mg to 1000 mg for oral administration, as injectablepreparations containing a dose of 0.1 mg to 500 mg or as suppositories,ointments, creams, gels or aerosol preparations.

This method affords especially a favourable treatment for inflammatoryphenomena and pain.

In human and animal therapeutics, the compounds of formula (I) can beadministered by themselves or in association with a physiologicallyacceptable excipient, in any form, in particular orally in the form ofgelatine capsules or tablets, or parenterally in the form of injectablesolutions. It is possible to envisage other forms of administration suchas suppositories, ointments, creams, gels or aerosol preparations.

As will be clearly apparent from the pharmacological experiments givenat the end of the description, the compounds according to the inventioncan be administered in human therapeutics, in the above-mentionedindications, orally in the form of tablets or gelatine capsulescontaining a dose of 1 mg to 1000 mg, or parenterally in the form ofinjectable preparations containing a dose of 0.1 mg to 500 mg, in one ormore daily dosage units, for an adult with an average weight of 60 to 70kg.

In animal therapeutics, the daily dose which can be used is between 0.1mg and 100 mg per kg.

Further characteristics and advantages of the invention will beunderstood more clearly by reading the following Examples, which in noway imply a limitation but are given by way of illustration.

EXAMPLE 1 4-chloro-4'-methylthiobenzophenone

Formula (III): A=4-chlorophenyl, R'═CH₃

To a solution of 105.8 g (0.852 mole) of thioanisole and 156.52 g (0.894mole) of 4-chlorobenzoyl chloride in 600 ml of dichloromethane, areadded 130.6 g (0.980 mole) of aluminium chloride in maintaining thetemperature between 0° C. and 5° C. The mixture is then stirred for 2hours at room temperature, left to stand overnight and then heated underreflux for 6 hours. After cooling, the mixture is poured into an icedsolution of dilute hydrochloric acid. After separation, the aqueousphase is washed with dichloromethane and the organic phases arecombined, dried over magnesium sulphate and evaporated in vacuo to give196.8 g of 4-chloro-4'-methylthiobenzophenone as crystals with a meltingpoint of 134° C.

EXAMPLE 2 4-chloro-4'-methanesulphonylbenzophenone

Formula (IV): A=4-chlorophenyl, R'═CH₃

To a solution of 40 g (0.152 mole) of4-chloro-4'-methylthiobenzophenone, prepared in example 1, in 700 ml ofdichloromethane, are added 82.6 g (0.335 mole) of 70% 3-chloroperbenzoicacid in maintaining the temperature at less than 5° C. The mixture isthen stirred at room temperature for 4 hours and the crystals arefiltered off. The filtrate is washed with sodium carbonate solution,dried over magnesium sulphate and evaporated in vacuo to give 42.5 g of4-chloro-4'-methanesulphonylbenzophenone as crystals with a meltingpoint of 176° C.

EXAMPLE 3(Z)-3-ethoxycarbonyl-4-(4-chlorophenyl)-4-(4-methanesulphonyl-phenyl)but-3-enoicacid

Formula (V) A=4-chlorophenyl, R'═CH₃, R'₁ ═C₂ H₅

341.5 g (1.16 moles) of 4-chloro-4'-methanesulphonylbenzophenone,prepared in example 2, 310 ml (1.85 moles) of ethyl succinate and 195.5g (1.74 moles) of potassium t-butoxide are successively added to 2.5litres of t-butanol. The temperature rises to 40-45° C., the mixture isstirred for 7 hours at room temperature after this exothermic reactionand is then poured into iced water. After acidification to pH 3 withhydrochloric acid, the mixture is extracted with diethyl ether. Theorganic phase is washed with water, dried over magnesium sulphate andevaporated in vacuo. The oil obtained is dissolved in diethyl ether andthen left overnight at room temperature. The crystals formed arefiltered off and dried to provide 102 g of(Z)-3-ethoxycarbonyl-4-(4-chlorophenyl)-4-(4-methanesulphonylphenyl)but-3-enoicacid as crystals with a melting point of 184-186° C. afterrecrystallisation from isopropanol. The evaporation of the filtrateallows the recovery of 219 g of a mixture consisting of 82% of the(E)-isomer and 18% of the (Z)-isomer.

EXAMPLE 4 Ethyl(Z)-3-(4-chlorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate

Formula (I): R═CH₃ ; A=4-chlorophenyl; Y═CO₂ Et

To a solution of 32.8 g (0.0775 mole) of(Z)-3-ethoxycarbonyl-4-(4-chlorophenyl)-4-(4-methanesulphonylphenyl)but-3-enoicacid, prepared in example 3, in 90 ml of anhydrous tetrahydrofuran areadded dropwise 15.5 ml (0.155 mole) of borane/dimethyl sulphide complex.The mixture is stirred at room temperature for 8 hours and 23.5 ml ofmethanol are added dropwise. The mixture is evaporated to dryness invacuo and the residue is dissolved in ethyl acetate. After washing withpotassium carbonate solution, the organic phase is separated, dried overmagnesium sulphate and evaporated in vacuo to give 30.8 g of ethyl(Z)-3-(4-chlorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoateas crystals with a melting point of 128° C. after recrystallisation fromisopropanol.

EXAMPLE 5 Sodium(Z)-3-(4-chlorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate

Formula (I): R═CH₃ ; A=4-chlorophenyl; Y═CO₂ H

To a solution of 5 g (0.0122 mole) of ethyl(Z)-3-(4-chlorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate,prepared in example 4, in 10 ml of ethanol are added 11 ml (0.011 mole)of 1 M sodium hydroxide. The mixture is heated for 2 hours under reflux,then evaporated to dryness in vacuo. The crystals obtained are washedwith ethyl acetate and with diethyl ether and then dried to provide 4.5g of sodium(Z)-3-(4-chlorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoateas crystals with melting point of 257-259° C.

EXAMPLE 6 4-fluoro-4 '-methylthiobenzophenone

Formula (III): A=4-fluorophenyl; R'═CH₃

Prepared according to the method of example 1.

Crystals with a melting point of 88° C.

EXAMPLE 7 4-fluoro-4 '-methanesulphonylbenzophenone

Formula (IV): A=4-fluorophenyl; R'═CH₃.

Prepared according to the method of example 2.

Crystals with a melting point of 136° C.

EXAMPLE 8(E)-3-ethoxycarbonyl-4-(4-fluorophenyl)-4-(4-methanesulphonyl-phenyl)but-3-enoicacid

Formula (V): A=4-fluorophenyl; R'═CH₃ ; R'₁ C₂ H₅

Prepared according to the method of example 3.

Crystals with a melting point of 155-156° C.

EXAMPLE 9 Ethyl(E)-3-(4-fluorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate

Formula (I): R═CH₃ ; A═4-fluorophenyl; Y═CO₂ Et

Prepared according to the method of example 4.

Crystals with a melting point of 100° C.

EXAMPLE 10 Sodium(E)-3-(4-fluorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate

Formula (I): R═CH₃ ; A=4-fluorophenyl; Y═CO₂ H

Prepared according to the method of example 5.

Crystals with a melting point of 268-269° C.

EXAMPLE 11 3,5-dichloro-4'-methylthiobenzophenone

Formula (III): A=3,5-dichlorophenyl; R'═CH₃

Prepared according to the method of example 1.

Crystals with a melting point of 108° C.

EXAMPLE 12 3,5-dichloro-4'-methanesulphonylbenzophenone

Formula (IV): A=3,5-dichlorophenyl; R'═CH₃.

Prepared according to the method of example 2.

Crystals with a melting point of 200° C.

EXAMPLE 13(Z)-3-ethoxycarbonyl-4-(3,5-dichlorophenyl)-4-(4-methanesulphonylphenyl)but-3-enoicacid

Formula (V): A=3,5-dichlorophenyl; R'═CH₃ ; R'₁ ═ C₂ H₅

Prepared according to the method of example 3.

Crystals with a melting point of 178° C.

EXAMPLE 14 Ethyl(Z)-3-(3,5-dichlorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate

Formula (I): R═CH₃ ; A=3,5-dichlorophenyl; Y═CO₂ Et

Prepared according to the method of example 4.

Crystals with a melting point of 130° C.

EXAMPLE 15 Sodium(Z)-3-(3,5-dichlorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate

Formula (I): R═CH₃ ; A=3,5-dichlorophenyl; Y═CO₂ H

Prepared according to the method of example 5.

Crystals with a melting point of 207-209° C.

EXAMPLE 16 4-benzylthiobenzonitrile

A mixture of 37.2 g of benzylmercaptan, 36.3 g of 4-fluorobenzonitrileand 42 g of potassium carbonate in 700 ml of butan-2-one is held underreflux for 7 hours. The solvent is evaporated in vacuo, the residue istaken up into water and petroleum ether. The crystals formed arefiltered off, washed with water and petroleum ether to give 46 g of4-benzylthiobenzonitrile as crystals with a melting point of 85° C.

EXAMPLE 17 4-benzylthio-4'-fluorobenzophenone

To a suspension of 9.6 g of magnesium turnings in 20 ml of anhydrousdiethyl ether is added dropwise a solution of 44 ml of4-bromo-1-fluorobenzene in 300 ml of anhydrous diethyl ether. At the endof the addition, the mixture is stirred for a few minutes at roomtemperature and a solution of 46 g of 4-benzylthiobenzonitrile, preparedin example 16, in 400 ml of anhydrous tetrahydrofuran is added dropwise.The diethyl ether is distilled off and the mixture is heated underreflux for 3 hours before being cooled with ice. A 6 M solution ofhydrochloric acid (400 ml) is added dropwise and the mixture is heatedunder reflux for 6 hours. After the addition of water anddichloromethane, the organic phase is separated, dried over magnesiumsulphate and evaporated in vacuo. The residue crystallises indiisopropyl ether to give 48 g of 4-benzylthio-4'-fluorobenzophenone ascrystals with a melting point of 96° C.

EXAMPLE 18 4-(1,1-dimethylethyl)sulphamoyl-4'-fluorobenzophenone

Chlorine is bubbled into a solution of 43 g of4-benzylthio-4'-fluorobenzophenone, prepared in example 17, in 300 ml ofacetic acid cooled to 0° C., until saturation (36 g). The mixture isthen stirred for two hours at room temperature and then poured into icedwater and extracted with dichloromethane. The organic phase is washedwith water, dried over magnesium sulphate and evaporated in vacuo togive 47 g of an oil which is dissolved in 100 ml of 1,2-dichloroethane.This solution is added dropwise to a solution of 50 ml of t-butylaminein 300 ml of 1,2-dichloroethane. The mixture is heated for one hour at80° C., cooled and washed with water then with dilute hydrochloric acid.The organic phase is dried over magnesium sulphate and evaporated invacuo. The residue crystallises in diethyl ether to give 25 g of4-(1,1-dimethylethyl)sulphamoyl-4'-fluorobenzophenone as crystals with amelting point of 160° C.

EXAMPLE 19(E)-3-ethoxycarbonyl-4-(4-(1,1-dimethylethyl)sulphamoylphenyl)-4-(4-fluorophenyl)but-3-enoicacid

Formula (VI): A=4-fluorophenyl, R'₁ ═C₂ H₅

Prepared according to the method of example 3, using two equivalents ofpotassium tert-butoxide.

Amorphous powder used as such in the next step.

EXAMPLE 20 Ethyl(E)-3-(4-(1,1-dimethylethyl)sulphamoylphenyl)-3-(4-fluorophenyl)-2-(2-hydroxyethyl)prop-2-enoate

Formula (VII): A=4-flurophenyl, R'₁ ═C₂ H₅

Prepared according to the method of example 4.

Oil used as such in the next step.

EXAMPLE 21(E)-3-[1-(4-sulphamoylphenyl)-1-(4-fluorophenyl)methylene]-dihydrofuran-2-one

Formula (VIII): A=4-fluorophenyl

A solution of 10 g of ethyl(E)-3-(4-(1,1-dimethylethyl)sulphamoylphenyl)-3-(4-fluorophenyl)-2-(2-hydroxyethyl)prop-2-enoate,prepared in example 20, in 50 ml of trifluoroacetic acid is heated underreflux for 16 hours. The solution is evaporated to dryness in vacuo andthe residue is taken up into an acetone/diethyl ether mixture. Thecrystals formed are filtered off and dried to give 5.1 g of(E)-3-[1-(4-sulphamoylphenyl)-1-(4-fluorophenyl)methylene]-dihydrofuran-2-oneas crystals with a melting point of 202° C.

EXAMPLE 22(E)-3-(4-sulphamoylphenyl)-3-(4-fluorophenyl)-2-(2-hydroxyethyl)prop-2-enoicacid

Formula (I): R═NH₂, A=4-fluorophenyl, Y═CO₂ H

Prepared according to the method of example 5 from(E)-3-[1-(4-sulphamoylphenyl)-1-(4-fluorophenyl)methylene]-dihydrofuran-2-one,prepared in example 21. The sodium salt obtained is treated with dilutehydrochloric acid and is extracted with dichloromethane, the solvent isevaporated in vacuo to give(E)-3-(4-sulphamoylphenyl)-3-(4-fluorophenyl)-2-(2-hydroxy-ethyl)prop-2-enoicacid as crystals with a melting point of 160-162° C.

EXAMPLE 23 3,4-dichloro-4'-methylthiobenzophenone

Formula (III): A═3,4-dichlorophenyl, R'═CH₃

Prepared according to the method of example 1.

Crystals with a melting point of 108° C.

EXAMPLE 24 3,4-dichloro-4'-methanesulphonylbenzophenone

Formula (IV): A=3,4-dichlorophenyl, R'═CH₃

Prepared according to the method of example 2.

Crystals with a melting point of 148° C.

EXAMPLE 25(Z)-3-ethoxycarbonyl-4-(3,4-dichlorophenyl)-4-(4-methanesulphonylphenyl)but-3-enoicacid

Formula (V): A═3,4-dichlorophenyl, R'═CH₃, R'₁ ═C₂ H₅

Prepared according to the method of example 3.

Oil used as such in the next step.

EXAMPLE 26 Ethyl(Z)-3-(3,4-dichlorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate

Formula (I): R═CH₃, A═3,4-dichlorophenyl, Y═CO₂ Et

Prepared according to the method of example 4.

Oil used as such in the next step.

EXAMPLE 27 Sodium(Z)-3-(3,4-dichlorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate

Formula (I): R═CH₃, A=3,4-dichlorophenyl, Y═CO₂ H

Prepared according to the method of example 5.

Crystals with a melting point of 264-266° C.

EXAMPLE 28(Z)-2-[1-(4-chlorophenyl)-1-(4-methanesulphonylphenyl)methylene]succinicacid

Formula (V): A=4-chlorophenyl, R'═CH₃, R'₁ ═H

To a suspension of 50 g (0.118 mole) of(Z)-3-ethoxycarbonyl-4-(4-chlorophenyl)-4-(4-methanesulphonylphenyl)-3-butenoicacid, prepared in example 3, in 1000 ml of ethanol is added a solutionof 10.4 g (0.26 mole) of sodium hydroxide in 25 ml of water. The mixtureis heated under reflux for 6 hours, the precipitate is filtered off andwashed with ethanol. The solid is then taken up into 500 ml of a 1Nsodium hydroxide solution and the insoluble is filtered off. The aqueousphase is washed with dichloromethane and then acidified withhydrochloric acid to pH=1. After one hour's stirring, the precipitateobtained is filtered under suction, washed with water and dried to give38.4 g of(Z)-2-[1-(4-chlorophenyl)-1-(4-methanesulphonylphenyl)-methylene]succinicacid in the form of crystals with a melting point of 199-200° C.

EXAMPLE 29(Z)-2-[1-(4-chlorophenyl)-1-(4-methanesulphonylphenyl)methylene]-1,4-butanediol

Formula (I): R═CH₃, A=4-chlorophenyl, Y═CH₂ OH

To a solution of 7.85 g (0.0199 mole) of(Z)-2-[1-(4-chlorophenyl)-1-(4-methanesulphonylphenyl)methylene]succinicacid, prepared in example 28, in 40 ml of tetrahydrofuran are addeddropwise 5.65 ml (0.0596 mole) of borane/dimethyl sulphide complex. Themixture is then stirred for 3 hours at ambient temperature and then 1hour at 50° C. After returning to ambient temperature, 5 ml of ethanolare added dropwise. The mixture is then concentrated to half its volumeand then taken up into water. The crystals obtained are filtered offunder suction and washed with pentane and dried giving 6.92 g of(Z)-2-[1-(4-chlorophenyl)-1-(4-methanesulphonylphenyl)-methylene]-1,4-butanediolin the form of crystals with a melting point of 159-160° C.

EXAMPLE 30 3-chloro-4-methoxy-4'-methylthiobenzophenone

Formula (III): 3-chloro-4-methoxyphenyl, R'═CH₃

Prepared according to the method of example 1 from3-chloro-4-methoxybenzoyl chloride.

Crystals with a melting point of 100° C.

EXAMPLE 31 3-chloro-4-methoxy-4'-methanesulphonylbenzophenone

Formula (IV): A=3-chloro-4-methoxyphenyl, R'═CH₃

Crystals with a melting point of 164° C.

EXAMPLE 32(Z)-3-ethoxycarbonyl-4-(3-chloro-4-methoxyphenyl)-4-(4-methanesulphonylphenyl)-3-butenoicacid

Formula (V): A=3-chloro-4-methoxyphenyl, R'═CH₃, R'₁ ═C₂ H₅

Prepared according to the method of example 3.

Crystals with a melting point of 179° C.

EXAMPLE 33 Ethyl(Z)-3-(3-chloro-4-methoxyphenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)-2-propenoate

Formula (I): R═CH₃, A=3-chloro-4-methoxyphenyl, Y═CO₂ Et

Prepared according to the method of example 4.

Crystals with a melting point of 102° C.

EXAMPLE 34 4-benzylthio-3'-methylbenzophenone

Prepared according to the method of example 17 from 3-bromotoluene.

Crystals with a melting point of 95° C.

EXAMPLE 35 4-(1,1-dimethylethyl)sulphamoyl-3'-methylbenzophenone

Prepared according to the method of example 18 from4-benzylthio-3'-methylbenzophenone prepared in example 34.

Crystals with a melting point of 144° C.

EXAMPLE 363-ethoxycarbonyl-4-(4-(1,1-dimethylethyl)sulphamoylphenyl)-4-(3-methylphenyl)-3-butenoicacid

Formula (VI): A=3-methylphenyl, R'₁ ═C₂ H₅

Prepared according to the method of example 19.

Mixture of (E) and (Z) isomers in the form of an oil used as such in thenext step.

EXAMPLE 37 Ethyl3-(4-(1,1-dimethylethyl)sulphamoylphenyl)-3-(3-methylphenyl)-2-propenoate

Formula (VII): A=3-methylphenyl, R'₁ ═C₂ H₅

Prepared according to the method of example 20.

Mixture of (Z) and (E) isomers in the form of an oil used as such in thenext step.

EXAMPLE 38(Z)-3-[1-(4-sulphamoylphenyl)-1-(3-methylphenyl)methylene]-dihydrofuran-2-one

Formula (VIII): A=3-methylphenyl

Prepared according to the method of example 21.

The mixture of (Z) and (E) isomers is chromatographed on silica elutingwith dichloromethane/acetone (10/1) to give the (Z) isomer in the formof crystals with a melting point of 161° C.

EXAMPLE 39(Z)-3-(4-sulphamoylphenyl)-3-(3-methylphenyl)-2-(2-hydroxyethyl)-2-propenoicacid

Formula (I): R═NH₂, A=3-methylphenyl, Y═CO₂ H

Prepared according to the method of example 22.

Crystals with a melting point of 117-118° C.

EXAMPLE 40 4-benzylthio-4'-methylbenzophenone

Prepared according to the method of example 17 from 4-bromotoluene.

Crystals with a melting point of 110° C.

EXAMPLE 41 4-(1,1-dimethylethyl)sulphamoyl-4'-methylbenzophenone

Prepared according to the method of example 18 from4-benzylthio-4'-benzophenone prepared in example 40.

Crystals with a melting point of 120° C.

EXAMPLE 423-Ethoxycarbonyl-4-(4-(1,1-dimethylethyl)sulphamoylphenyl)-4-(4-methylphenyl)-3-butenoicacid

Formula (VI): A=4-methylphenyl, R'₁ ═C₂ H5

Prepared according to the method of example 19.

Mixture of (E) and (Z) isomers in the form of an oil used as such in thenext step.

EXAMPLE 43 Ethyl3-(4-(1,1-dimethylethyl)sulphamoylphenyl)-3-(4-methylphenyl)-2-(2-hydroxyethyl)-2-propenoate

Formula (VII): A=4-methylphenyl, R'₁ ═C₂ H₅

Prepared according to the method of example 20.

Mixture of (E) and (Z) isomers in the form of an oil used as such in thenext step.

EXAMPLE 44(Z)-3-[1-(4-sulphamoylphenyl)-1-(4-methylphenyl)methylene]-dihydrofuran-2-one

Formula (VIII): A=4-methylphenyl

Prepared according to the method of example 21.

The mixture of (Z) and (E) isomers is chromatographed on silica elutingwith dichloromethane/acetone (10/1) giving the (Z) isomer in the form ofcrystals with a melting point of 159° C.

EXAMPLE 45(Z)-3-(4-sulphamoylphenyl)-3-(4-methylphenyl)-2-(2-hydroxyethyl)-2-propenoicacid

Formula (I): R═NH₂, A=4-methylphenyl, Y═CO₂ H

Prepared according to the method of example 22.

Obtained in an amorphous form.

PHARMACOLOGY

The anti-inflammatory activity of the compounds of the Examples has beenevaluated according to the method of oedema with carrageenan and theanalgesic activity has been evaluated according to the method ofarthritis with kaolin.

Methods

Anti-Inflammatory Activity

The anti-inflammatory activity is evaluated in rats by the test ofoedema with carrageenan. The product is administered orally at a rate of2.5 ml/100 g (n=6 animals per dose) 2 hours 30 minutes after a wateroverload taken orally (2.5 ml/ 100 g). One hour after administration ofthe product, the oedema is induced by plantar subcutaneous injection ofaqueous 2% carrageenan solution. The percentage inhibition of the volumeof the oedema is calculated after 3 hours by measuring the volume of thepaw with the aid of a mercury plethysmometer.

Analgesic Activity

The analgesic activity is evaluated in rats by the test of arthritiswith kaolin. Thirty minutes after intra-articular administration of anaqueous 10% suspension of kaolin, the product is administered orally ata rate of 1 ml/100 g (n=10 animals per dose). The percentage inhibitionof the animal's pain response (by rating the way it walks) is calculated5 hours 30 minutes after administration of the product.

    ______________________________________                                                Dose    Anti-inflammatory activity                                                                    Analgesic activity                            Example (mg/kg) % inhibition    % inhibition                                  ______________________________________                                        14       30     28.9 ± 4.5   45.8 ± 10.9                                27      100     32.4 ± 8.2   63.6 ± 13.2                                ______________________________________                                    

Inhibition Of The COX-1 and COX-2 Enzymatic Activities

The molecule studied is preincubated for 10 minutes at 25° C. with 2 Uof COX-1 (purified enzyme from ram seminal vesicles) or 1 U of COX-2(purified enzyme from ewe placenta). Arachidonic acid (6 μM for COX-1,4, μM for COX-2) is added to the reaction medium and incubation iscarried out for 5 minutes at 25° C. When incubation has ended, theenzymatic reaction is stopped by the addition of 1 N HCl and the PGE2produced is determined by EIA.

The results are expressed as the percentage inhibition of the COX-1 andCOX-2 enzymatic activities and correspond to mean (±) standarddeviations from the average of 4 determinations.

    ______________________________________                                                % inhibition of   % inhibition of                                             COX-2 activity    COX-1 activity                                      Example   10.sup.-5 M                                                                           10.sup.-7 M   10.sup.-5 M                                                                         10.sup.-7 M                             ______________________________________                                        14        80 ± 2                                                                             16 ± 9     0 ± 0                                                                            0 ± 0                                ______________________________________                                    

TOXICOLOGY

The first toxicology studies performed show that the products of theExamples do not induce a deleterious effect in the rat after the oralabsorption of doses ranging up to 300 mg/kg.

We claim:
 1. A 1,2 diarylmethylene compound of formula (I): ##STR20##wherein: R is:a lower alkyl radical having 1 to 6 carbon atoms, a lowerhaloalkyl radical having 1 to 6 carbon atoms, or an --NH₂ group,##STR21## A is a thiophene or pyridine heterocycle ##STR22## wherein X₁,X₂ and X₃ independently are: the hydrogen atom, a halogen atom, a loweralkyl radical having 1 to 6 carbon atoms, lower O-alkyl radical having 1to 6 carbon atoms or a trifluoromethyl radical, or even two of thesetogether form a methylene dioxy group, Y is:a CO₂ R₁ group wherein R₁ isselected from the group consisting of the hydrogen atom and a loweralkyl radical having 1 to 6 carbon atoms, a --CH₂ OH group, or apharmaceutically acceptable salt thereof.
 2. A compound of formula (I)according to claim 1, wherein:R is:a methyl radical, or an NH₂ group, Ais a thiophene or pyridine heterocycle ##STR23## wherein X₁ and X₂independently are a hydrogen atom,a halogen atom, a lower O-alkylradical having from 1 to 6 carbon atoms, or a lower alkyl radical havingfrom 1 to 6 carbon atoms, Y isa --CO₂ R₁ group wherein R₁ is selectedfrom the group consisting of a hydrogen atom or a lower alkyl radicalhaving 1 to 6 carbon atoms, or a CH₂ OH group, or a pharmaceuticallyacceptable salt thereof.
 3. A compound according to claim 1, wherein Ris selected from the group consisting of a methyl group or an --NH₂group.
 4. A compound according to claim 1, wherein A is an aromaticring: ##STR24## wherein X₁ is selected from the group consisting of achlorine atom or a fluorine atom, and X₂ is selected from the groupconsisting of a hydrogen atom or a chlorine atom.
 5. A compoundaccording to claim 1, wherein Y is selected from the group consisting ofthe --COOC₂ H₅ or the --COOH group and its salts.
 6. A pharmaceuticalcomposition, which comprises a pharmaceutically effective amount of atleast one compound of formula (I) such as defined in claim 1, or apharmaceutically acceptable salt thereof, incorporated in apharmaceutically acceptable excipient, vehicle or carrier.
 7. Apharmaceutical composition with anti-inflammatory and analgesicactivity, which comprises a pharmaceutically effective amount of acompound of formula (I) as defined in claim 1, or a pharmaceuticallyacceptable salt thereof, incorporated in a pharmaceutically acceptableexcipient, vehicle or carrier.
 8. A pharmaceutical composition accordingto claim 6, which is presented in the form of gelatin capsules ortablets containing a dose of 1 mg to 1,000 mg.
 9. A pharmaceuticalcomposition according to claim 6, which is presented in the form ofinjectable preparations containing a dose of 0.1 mg to 500 mg.